Anti-retroviral nucleoside analogs are widely used in the treatment of AIDS. However, anti-retroviral nucleoside therapy often must be discontinued because it induces a debilitating painful peripheral neuropathy for which no adequate therapy is available. To facilitate the rational design of pharmacological strategies to treat or prevent nucleoside-induced neuropathic pain, we will perform a series of experiments to elucidate the cellular mechanisms of nucleoside-induced painful neuropathy. Specifically, we will establish a model of painful peripheral neuropathy induced by anti-retroviral nucleosides in the rat. We will then analyze nucleoside-induced changes in the excitability of nociceptive nerve fibers in this model. Guided by that analysis, we will employ patch-clamp recording of cultured sensory neurons to study the effects of antiretroviral nucleosides on specific transduction molecules and ion channels. Those studies will establish a behavioral and cellular model of anti-retroviral nucleoside-induced painful neuropathy that will enable our proposed experiments to investigate intracellular second messenger systems and ion channels that produce the nucleoside-induced hyperalgesia and nociceptor hyperexcitability. Because nucleoside-induced neuropathy can be exacerbated by common comorbidities in this population of patients, including neuropathies induced by diabetes mellitus, and alcoholism, we will also evaluate interactions between nucleoside-induced neuropathy and these comorbid neuropathies. Our laboratory has extensive expertise in the full range of in vivo and in vitro methods to be employed, has successfully developed experimental models of peripheral neuropathies, and has performed investigations of second messengers involved in models of painful peripheral neuropathies induced by diabetes, alcohol, and vincristine, and in inflammatory hyperalgesic states. In addition to their great potential clinical significance, these studies should also provide basic insights into cellular mechanisms controlling neuronal excitability.